MEN1, MEN2A and MEN2B: match the gene to its tumours

MEN1, MEN2A and MEN2B: the case and the goal

A 30-year-old woman has her second kidney stone. Her serum calcium is 11.8 mg/dL, and her father once had a pituitary tumour. Two glands are involved in one family. Is a third tumour waiting in her pancreas?

This lesson covers MEN1, MEN2A and MEN2B: how to match each syndrome to its gene and to its tumours.^[1][2]

What multiple endocrine neoplasia means

Multiple endocrine neoplasia means that several endocrine glands form tumours in the same patient, and in the same family.^[1][2]

All three syndromes are autosomal dominant and are caused by a germline mutation. Each child of a carrier therefore has a one in two chance of inheriting it.^[1][2]

So the first question for any patient with tumours in more than one endocrine gland is whether one of the three syndromes fits. The answer comes from two things: which gene is involved, and which glands are affected.^[1][2]

Two genes: a lost brake and a jammed accelerator

Only two genes matter here. The MEN1 gene lies on chromosome 11. It encodes menin, a tumour suppressor, and the mutation is loss of function. A tumour forms once the second copy is lost.^[1][2]

The RET gene lies on chromosome 10. RET is a proto-oncogene that encodes a receptor tyrosine kinase, and the mutations are activating.^[2][3]

In short, MEN1 loses a brake, and MEN2 jams the accelerator. Each gene brings its own set of tumours, and that is what makes the combinations predictable.^[1][2][3]

MEN1: the three P's

The MEN1 pattern is remembered as the three P's: parathyroid, pituitary and pancreas. Loss of menin affects all three.^[1][2]

• Parathyroid: multigland hyperplasia causing primary hyperparathyroidism. It is found in nearly everyone and is the most common manifestation.^[1][2]
• Pituitary: adenomas, most often prolactinomas or non-functioning tumours.^[1][2]
• Pancreas: duodenopancreatic neuroendocrine tumours, such as a gastrinoma, which causes Zollinger-Ellison syndrome, or an insulinoma.^[1][2]

That is the opening patient: a high calcium and a family pituitary tumour point to MEN1, which a gene test would confirm, and her pancreas needs watching.

MEN2: RET, its core tumours, and MEN2A versus MEN2B

MEN2A and MEN2B share two tumours.

• Medullary thyroid carcinoma, from the calcitonin-secreting C cells, with near-total penetrance.^[2][3]
• Pheochromocytoma, in 20–50% of patients: a tumour of the adrenal medulla, almost always in the adrenal gland and rarely malignant.^[2][3]

These two tumours are the MEN2 core. Whenever RET is the gene, think of medullary thyroid carcinoma first, and then of pheochromocytoma. Parathyroid disease, neuromas and body habitus are what separate 2A from 2B.^[2][3]

MEN2A adds parathyroid tumours, so primary hyperparathyroidism again. Most cases carry a mutation in RET codon 634.^[2][3]

MEN2B has no parathyroid disease. Instead it adds mucosal neuromas and a Marfanoid body habitus. Nearly all cases carry one mutation, methionine 918 threonine (M918T), usually new in that patient. It is the most aggressive form, and medullary cancer can appear in the first year of life.^[2][3]

Why it matters: calcitonin, and pheochromocytoma before thyroid surgery

Calcitonin tracks the medullary thyroid carcinoma.^[2][3]

The order matters because a pheochromocytoma that goes unrecognised can turn the anaesthetic for thyroid surgery into an emergency. Testing for it first removes that risk, and it is the rule to apply in the worked example below and in the practice question.^[3][4]

Worked example: a thyroid nodule and a high calcium

The worked example links each finding to a tumour, and then the combination to a syndrome: medullary carcinoma, probable pheochromocytoma and hypercalcaemia point to RET and MEN2A. The same logic works in reverse: first name the gene, then list the tumours it brings.^[2][3]